Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2
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Daibiao Xiao1, Ping Ren2, Hexiu Su3, Ming Yue1, Ruijuan Xiu1, Yufeng Hu3, Hudan Liu3,4, Guoliang Qing1,4
1School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
2Department of Pharmacology, School of Pharmacy, Hubei University of Science & Technology, Xianning 437100, China
3School of Pharmacy, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
4Medical Research Institute, Wuhan University, Wuhan 430071, China
Guoliang Qing, e-mail: email@example.com
Keywords: neuroblastoma, N-Myc, glutaminase 2, glutamine, cancer metabolism
Received: May 09, 2015 Accepted: September 23, 2015 Published: October 19, 2015
Deamidation of glutamine to glutamate by glutaminase 1 (GLS1, also called GLS) and GLS2 is an essential step in both glutaminolysis and glutathione (GSH) biosynthesis. However, mechanisms whereby cancer cells regulate glutamine catabolism remains largely unknown. We report here that N-Myc, an essential Myc family member, promotes conversion of glutamine to glutamate in MYCN-amplified neuroblastoma cells by directly activating GLS2, but not GLS1, transcription. Abrogation of GLS2 function profoundly inhibited glutaminolysis, which resulted in feedback inhibition of aerobic glycolysis likely due to thioredoxin-interacting protein (TXNIP) activation, dramatically decreasing cell proliferation and survival in vitro and in vivo. Moreover, elevated GLS2 expression is significantly elevated in MYCN-amplified neuroblastomas in comparison with non-amplified ones, correlating with unfavorable patient survival. In aggregate, these results reveal a novel mechanism deciphering context-dependent regulation of metabolic heterogeneities, uncovering a previously unsuspected link between Myc, GLS2 and tumor metabolism.
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